Fatigue is a factor that affects nurse performance in the workplace. Previous research has investigated the relationships between work system parameters and fatigue; however, no study has considered multiple work system parameters simultaneously, and how they affect multiple dimensions of fatigue. This study used Chi-Squared Automatic Interaction Detection (CHAID) to mine work system parameters and their multiple interactions on perceptions of mental, physical, and total fatigue dimensions in registered nurses. Results showed that multiple work system parameters were associated with changes in fatigue levels across mental, physical, and total fatigue dimensions. These findings expand our understanding of the relationships between work system parameters and fatigue and provide valuable information to improve the design of nursing work systems, in order to retain qualified nursing personnel and ultimately improve both patient- and provider safety.